1—The Role of IL-23 in the Immune System
IL-23 is a recently discovered cytokine, secreted mainly by activated dendritic cells, monocytes and macrophages. It comprises two subunits linked by a disulfide bond, designated by p19 and p40 (Oppmann B et al., Immunity, 13(5), pp 715-25, 2000). The human p40 subunit contains 328 amino-acids and is shared between the cytokine IL-12 and IL-23. The human p19 subunit, which contains 189 amino-acids, is specific of IL-23 and participates in the binding of IL-23 with its receptor (Parham C et al., J Immunol, 168(11), pp 5699-708, 2002). IL-23 is known to promote a specific T cell activation state characterized by the production of IL-17, a cytokine frequently over-expressed in several inflammatory diseases (Aggarwal S et al., 278(3), pp 1910-4, 2003). IL-23 acts preferentially on memory T cells rather than on naïve T cells, supporting its role in long term inflammation and in particular in the survival and expansion of autoreactive cells in autoimmune disorders.
Initial findings showed that the transgenic expression of IL-23 in an animal model induces a severe systemic inflammation marked notably in many key organs such as the skin or the digestive tract (Wiekowski M T et al., J Immunol, 166(12), pp 7563-70, 2001). These findings prompted the investigators to study a possible role for IL-23 in diseases like psoriasis or inflammatory bowel disease. Today it is well known that IL-23 drives the inflammatory events leading to severe intestinal inflammation in mice (Kullberg M C et al., J Exp Med, 203(11), pp 2485-94, 2006; Hue S et al., J Exp Med, 203(11), pp 2473-83, 2006) and that functional IL-23R variants are strongly linked to inflammatory bowel disease in human (Duerr R H et al., Science, 314(5804), pp 1461-3, 2006). Similarly, a disease-promoting role for IL-23 has been described in autoimmune inflammation in the brain (Cua D J et al., Nature, 421(6924), pp 744-8, 2003), in joints during autoimmune arthritis (Murphy C A et al., J Exp Med, 198(12), pp 1951-7, 2003), in the skin during psoriasis (Lee E et al., J Exp Med, 199(1), pp 125-30, 2004) and even in the incidence and growth of certain tumours (Langowski J L et al., Nature, 442(7101), pp 461-5, 2006). In addition, IL-23 is also known to play a role in the development of various diseases characterized by an excessive bone resorption, with or without inflammation, such as in osteoporosis (Kim et al. (2008) Exp Mol Med. 40:418-26). In contrast with the blockade of IL-12, the specific antagonism of IL-23 through its p19 subunit has indeed the potential of strongly improving many organ-specific diseases without compromising long-term protective responses in the patients.
2—Existing Antagonists of IL-23
In order to specifically block the activity of a desired cytokine, macromolecules and particularly antibodies or soluble receptors to this cytokine have been used. The therapeutic use of antibodies against the common subunit p40 of the human IL-12 and human IL-23 has been disclosed in International patent application WO 04/101750. Similarly, the use of inhibitory macromolecules binding to the subunit p19 of human IL-23 has been disclosed in patent applications WO 07/005,955, WO 08/103,473, and U.S. Ser. No. 09/012,3479. The use of monoclonal antibodies directed simultaneously against the subunits p19 and p40 or against the IL-23-specific receptor has also been disclosed in International patent application WO 04/042009. Finally, the use of antibodies against one or both human IL-23 and its downstream effector cytokine IL-17 has been disclosed in International patent application WO 07/027,761. An alternative approach to the passive infusion of inhibitors is to use an active immunization against cytokines as disclosed in International patent application WO 03/084979.
3—The Current Art in Active Immunization Against IL-23
A method of vaccination to fight autoimmune diseases, comprising the subunit p35 of IL-12 or the common subunit p40 for IL-12 and IL-23, has been disclosed in International patent application WO 05/058349. A method of vaccination against some IL-23 peptides has been previously disclosed by our group in International application WO 03/084979, in particular against the peptide LLP DSP VGQ LHA SLL GLS Q (SEQ ID NO: 1). Peptides derived from IL-23p19 are also disclosed in International application WO 2005/108425.